RT Journal Article
SR Electronic
T1 Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1800965
DO 10.1183/13993003.00965-2018
VO 53
IS 6
A1 Rita Papp
A1 Chandran Nagaraj
A1 Diana Zabini
A1 Bence M. Nagy
A1 Miklós Lengyel
A1 Davor Skofic Maurer
A1 Neha Sharma
A1 Bakytbek Egemnazarov
A1 Gabor Kovacs
A1 Grazyna Kwapiszewska
A1 Leigh M. Marsh
A1 Andelko Hrzenjak
A1 Gerald Höfler
A1 Miroslava Didiasova
A1 Malgorzata Wygrecka
A1 Laura K. Sievers
A1 Peter Szucs
A1 Péter Enyedi
A1 Bahil Ghanim
A1 Walter Klepetko
A1 Horst Olschewski
A1 Andrea Olschewski
YR 2019
UL http://erj.ersjournals.com/content/53/6/1800965.abstract
AB Our systematic analysis of anion channels and transporters in idiopathic pulmonary arterial hypertension (IPAH) showed marked upregulation of the Cl− channel TMEM16A gene. We hypothesised that TMEM16A overexpression might represent a novel vicious circle in the molecular pathways causing pulmonary arterial hypertension (PAH).We investigated healthy donor lungs (n=40) and recipient lungs with IPAH (n=38) for the expression of anion channel and transporter genes in small pulmonary arteries and pulmonary artery smooth muscle cells (PASMCs).In IPAH, TMEM16A was strongly upregulated and patch-clamp recordings confirmed an increased Cl− current in PASMCs (n=9–10). These cells were depolarised and could be repolarised by TMEM16A inhibitors or knock-down experiments (n=6–10). Inhibition/knock-down of TMEM16A reduced the proliferation of IPAH-PASMCs (n=6). Conversely, overexpression of TMEM16A in healthy donor PASMCs produced an IPAH-like phenotype. Chronic application of benzbromarone in two independent animal models significantly decreased right ventricular pressure and reversed remodelling of established pulmonary hypertension.Our findings suggest that increased TMEM16A expression and activity comprise an important pathologic mechanism underlying the vasoconstriction and remodelling of pulmonary arteries in PAH. Inhibition of TMEM16A represents a novel therapeutic approach to reverse remodelling in PAH.TMEM16A plays a central role in the pathological mechanisms underlying the depolarisation, vasoconstriction and proliferation of PASMCs, contributing to the increased pulmonary vascular resistance in PAH, thus providing a novel target for PAH therapy http://ow.ly/3Rs330o3CUy